Medicaments for asthma treatment

ABSTRACT

A method and apparatus are disclosed for treating asthma and other respiratory conditions. A medicament comprising a surface active phospholipid (SAPL) is prepared in the form of a fine powder and administered to the lungs in a gas stream. A preferred SAPL is a solid blend of diplamitoyl choline and phosphatdiyl glycerol (PG).

This invention relates to artificial lung surfactants and their use inthe treatment of asthma.

It has been estimated that asthma affects between 4 and 10 percent ofthe population, causing distress and alarm to both sufferers andbystanders. Asthma attacks appear to be precipitated in many cases by anumber of factors such as exercise or pollutants in the inspired air.Other agents such as pollen and airborne particles may predispose anasthma sufferer to an attack by sensitising the airways. This has led tothe belief that effective treatment: should include administration ofdrug which reduce the sensitivity of asthma sufferers to allergens orwhich neutralise the allergic reaction.

The present invention is based on a different approach namely that thelungs and always of non-asthmatics may contain a natural protectivebarrier which prevents pollutants and other airborne triggers fromreaching receptors whose irritation would then produce an acute attack.While not wishing to be bound by any fixed theory at this stage, studieshave suggested that SAPL masks (covers) most of these receptors innormal lungs but this masking is deficient in asthmatics. The presetinvention is predicted on the belief that it is possible to restore normasking by binding surface-active phospholipids (SAPL) to the tissuesurface of the lungs, thereby reducing the number of receptors exposedto noxious stimuli and reducing hyper-responsiveness of thebroncho-constrictor reflex, common to all forms of asthma.

SAPL's are used clinically for the treatment of neonates withrespiratory distress syndrome (RDS). In this role, it has been assumedthat the SAPL functions by reducing the high surface tension of theair-water interface within the alveoli, thereby reducing the pressureneeded to expand the lungs, see Milner, Archives of Diseases inChildhood 1993; 68-253. Thus, commercially available formulations ofSAPL have been designed to spread rapidly over an air-aqueous interface,thereby reducing what is otherwise a very high surface tension of water.

Limited clinical studies have been carried out to determine the effectof commercial SAPL's marketed for treatment of RDS in neonates onasthmatic subjects,—see Kurashima et al. Jap. J. Allergol 1991; 40, 160.This paper reported some amelioration of broncho-constriction inasthmatic adults using an SAPL obtained by extraction from bovine lungs.In another study on children, also using an SAPL obtained from bovinelungs, no significant changes in lung function or histamine responsewere found,—see Oetomo et al—American Journal of Respiratory andCritical Care Medicine 153; 1996, page 1148.

Our approach to tie problem differs from these studies in that itinvolves the use of an anti-asthma medicament which is capable ofbinding (absorbing) to the tissue suffice (epithelium) of the airways,thereby masking receptors against stimulation by noxious agents orsensitisation by allergenic stimuli. Although it is an advantage for themedicament employed in this invention to spread over the surfaces of theairways, once in place, one or more components of the composition willmigrate across the mucous layer and deposit a thin hydrophobic lining onthe tissue surface, and/or supplement the indigenous coating.

According to one of its aspects, the present invention comprises use ofa surface active phospholipid (SAPL) composition in the preparation of amedicament for the treatment of asthma by administration of themedicament to the patient's airways and upper respiratory tract, saidmedicament comprising SAPL and containing a component capable of bindingto the surface of lung tissue.

DETAILED DESCRIPTION OF DRAWINGS

FIG. 1. Apparatus for administering the surface-active agent.

FIG. 2. Interior view of device as shown in FIG. 1.

Examples of SAPL's which appear to be capable of forming a thin film orcoating on surfaces of the lungs include diacyl phosphatidyl cholines(DAPC's), e.g. dioleyl phosphatidyl choline (DOPC); distearylphosphatidyl choline (DSPC) and dipalmitoyl phosphatidyl choline (DPPC).The SAPL is preferably administered as a dry powder. Another preferredcomponent of the medicament is a spreading agent. Its function is toreduce the melting point of the DAPC so that it rapidly spreads as athin film at normal body temperature. Suitable spreading agents includephosphatidyl glycerols (PG); phosphatidyl ethanolamines (PE);phosphatidyl serines (PS) and phosphatidyl inositols (PI). Anotheruseful spreading agent is cholesteryl palmitate (CP). Alternatively, itis possible to reduce the melting temperature and hence improve thespreading characteristics of a DAPC by employing a DL mixture of thephospholipid. The above spreading agents, especially PG, are believed toenhance or potentiate the binding of the DAPC, especially the DPPC, tothe epithelial surface.

Dipalmitoyl phosphatidylcholine (DPPC) is believed to be capable ofbiding to lung tissue and is, therefore, a preferred component of theSAPL. Phosphatidyl glycerol (PG) may function also in this way and isalso a preferred component of the SAPL. PG has a further importantfunction in medicaments employed in the present invention and this isits ability to cause the SAPL to form a very finely-divided, dry powderdispersion in air. Such dispersions may have particle sizes in the rangeof 0.5 to 20 μm, preferably 0.5 to 5 μm and more preferably 0.5 to 2 μm.Typically, the median particle diameter is about 1.2 μm. Finely divideddry powders of this kind (which may be described as fumed powders) areadsorbed onto the surfaces of lung tissue, i.e. bound to the epithelium.

Preferably, the SAPL compositions employed in the present invention areblends of dipalmitoyl phosphatidylcholine (DPPC) and PG.

The medicament should generally be essentially free from animal proteinin order to avoid the danger of patient sensitivity to animal proteinand pyrogens. Also, surfactants which are derived from animal proteinsare not available in a finely-divided particle form which can bedispersed in a gas stream.

DPPC can be prepared synthetically by the use of acyl chlorides usingthe method of Baer & Bachrea—Can. J. Of Biochem. Physiol 1959; 37, page953 and is available commercially from Sigma (London) Ltd. The PG may beprepared from egg phosphatidylcholine by the methods of Comfurions et aland Dawson, Biochem. Biophys Acta 1977; 488; pages 36-42 and Biochem J.1947; 192; pages 205-210. When co-precipitated with DPPC from a commonsolvent such as chloroform, PG forms with DPPC a fine powder whichspreads rapidly over the surfaces of the airways and lungs. At a weightratio of DPPC:PG of about 7:3, the mixture spreads rapidly at atemperature of about 35° C. and above. Additional or lesser quantitiesof PG can be incorporated into the composition and finely-dividedcompositions obtained. In general, DPPC and PG may be present in aweight ratio of from 9:1 to 1:9. Other DAPC's and other spreading agentsmay be used in similar proportions. Compositions employed in currentlytested formulations have been in the weight ratio of from about 6:4 to8:2. A SAPL suitable for use in accordance with the invention isobtainable from Britannia Pharmaceutical Ltd., 41-51 Brighton Road,Redhill, Surrey, under the trade mark ‘Alec’.

Because we are concerned in the present invention to achieve a long termadsorption of the medicament on the lung surface, it is highly desirablethat the SAPL (or its active component) should not break down in theenvironment of the lungs. One of the factors which will reduce the lifeof a lining or coating will be the presence of enzymes, such asphospholipase A, capable of digesting DPPC and/or PG. Such enzymes onlyattack the laevo rotatory (L) form, which constitutes the naturallyoccurring form. Therefore, the medicament should preferably contain thedextro-rotatory (D) form or at least comprise a racemic mixture, whichis obtained by synthetic routes.

The medicaments employed in the present invention are generallyfinely-divided dry powders having a particle size distribution which issmall enough to be introduced into the airways and, preferably, deeplyinto the lungs in a gas stream from a dispersion device. Generally,medicaments are preferred in which the particle size distribution issuch that a major proportion are between 0.5 and 2 micrometres. Suitabledispersion devices may employ a propellant such as a halocarbon to formthe gas steam and may include a tapered discharge nozzle baffle or aventuri to accelerate particles through a discharge nozzle, and toremove oversized particles. Suitable halocarbons includehydrofluorocarbons, hydrofluorochlorocarbons and fluorochlorocarbonshaving a low boiling point, such as those marketed under the trade mark“Freon”. The medicament may be packaged with a propellant in apressurised aerosol container within the inhaler. Other inhalers have animpeller which mixes the powder into an air stream and delivers thepowder-laden air into the patient's airways—see, e.g. U.S. Pat. No.5,577,497.

The invention also includes a dispersion device for administering amedicament useful in the treatment of asthma which comprises a sterilecartridge containing finely-divided particles of an essentiallyprotein-free mixture of DPPC and PG, and means for introducing saidparticles into a gas stream as the patient inhales, said particlesincluding a majority having particle sizes within the range of 0.5 to 2μm.

A preferred method and apparatus for administering the medicamentinvolves dispersing the powdered medicament in a propellant gas stream.For example, a pressurised canister of a liquefied gas may be connectedto a vial containing the medicament. By releasing controlled amounts ofgas from the canister into the vial, increments of the medicaments areejected from the vial as a cloud of powder and may be inhaled by theuser.

A typical design of the dispenser is shown in the accompanying drawings,in which:

FIG. 1 is a side elevation of the dipenser; and

FIG. 2 is a similar view, but shows its interior.

In the drawings, a casing (1) is formed from two plastic mouldings (2 &3) which snap together to form a container for a pressurised canister(4) and a vial (5). Canister (4) contains a low boiling liquid,preferably a hydrofluorocarbon such as HFA-134a or HFC-227, undersufficient pressure to maintain the propellant liquid at normal roomtemperature. Vial (5) contains the powdered medicament, such as “Alec”Canister (4) has a release valve (6) which is received in a recess (7)so that finger pressure on the inverted end (8) of the canister willcause propellant to be released into a tube (9). Tube (9) is typically ahard plastics, e.g. pvc or polypropylene, tube of about 2˜3 mm outsidediameter and about 0.5 to 2 mm inside diameter. Tube (9) connects valve(6) with a fitting (10) and thence to a tube or needle (11) whichextends into the vial (5). Vial (5) may be closed with a rubber sealwhich is penetrated by the tube or needle (11) and self-seals around thetube or needle. A second needle or tube (12) extends part way into thevial through the rubber seal in the neck of the vial and connects with afitting (13). Fitting (13) discharges into a mouthpiece (14) which is acomfortable shape for the user to place in the mouth. When the patientis in need of medication, he places the mouthpiece (14) into his mouthand breaths and simultaneously depresses the canister (4). This causes acloud of medicament to be dispensed into the patient's airways. Fittings(10) and (13) may be valves. Valves (10) may be set to permit measuredquantities of propellant to enter the vial. Similarly, valve (13) may beset to release when the pressure in the vial reaches a predeterminedlevel. It will be appreciated that the dispenser can be used one-handedin an analogous manner to a conventional nebulizer.

In addition to the powdered SAPL, the vial may incorporate other knownpulmonary or respiratory medicaments such as ‘Salbutamol’,‘Beclomethasone, Corticosteroids, or other asthma drugs. It is, however,preferred to package the conventional asthma drug in the propellantcanister or in a capsule interposed between the propellant container andthe vial containing the SAPL. In this way, the lungs and airways receivea cloud of SAPL and an aerosol of the conventional drug sequentially orsimultaneously. This combined therapy gives both quick relief andlasting protection as the film of SAPL spreads over the lung tissue.Instead of packaging the SAPL in a multi-use via, it may be contained ina capsule, which may be a single use quantity, between the outlet fromthe propellant canister and the mouthpiece.

While the present invention has been described with particular referenceto the treatment of human patents for asthma, it is possible that theinvention may also be applicable to the treatment of other pulmonarydiseases or conditions such as rhinnitis.

The medicament of the present invention may also be employed in thetreatment of pulmonary conditions in other mammals. An example isreactive airway disease in horses.

1. A method of treating asthma comprising, providing a surface activephospholipid (SAPL) composition as a dry powder, said compositioncomprising a diacyl phosphatidyl choline (DPC) selected from the groupconsisting of dioleyl phosphatidyl choline (DOPC), distearylphosphatidyl choline (DSPC) and dipamitoyl phosphatidyl choline (DPPC),and a spreading agent for said DPC, said spreading agent being selectedfrom the group consisting of phosphatidyl glycerols (PG), phosphatidylethanolamines (PE), phosphatidyl serines (PS), phosphatidyl inositols(PI) and cholesteryl palmitate (CP); and administering said SAPLcomposition to the lungs of an asthma patient as an inhalable drypowder; whereby binding of SAPL to the tissue surfaces of the lungsforms a coating of SAPL on said surfaces thereby preventing pollutantsand other airborne triggers from reaching the receptors whose irritationwould produce an acute asthma attack and reducing the number of saidreceptors exposed to noxious stimuli and reducing hyper-responsivenessof the broncho-constrictor reflex.
 2. The method of claim 1, whereinsaid dry powder is introduced using a gas stream.
 3. The method of claim2, wherein the gas stream comprises a halocarbon which is gaseous atambient temperature.
 4. The method of claim 3, wherein the halocarbon istetrafluoroethane or heptafluoropropane.
 5. The method of claim 1,wherein the composition comprises particles between 0.5 and 10 μm insize.
 6. The method of claim 1, wherein said spreading agent is PG. 7.The method of claim 1, wherein said DPC is DPPC.
 8. The method of claim1, wherein said DPC is DPPC and said spreading agent is PG.
 9. Themethod of claim 8, wherein the PG is present in an amount sufficient tolower the temperature at which DPPC will spread spontaneously over asurface at normal mammalian blood temperature.
 10. The method of claim8, wherein the DPPC and PG arepresent in a weight ratio of from about6:4 to 8:2.
 11. The method of claim 8, wherein the composition isprepared by forming a solution of the DPPC and the PG in a commonsolvent and recovering particles from the solution containing a mixtureof DPPC and PG.
 12. The method of claim 1, wherein at least onecomponent of the SAPL is in the D form or is a DL mixture.
 13. A methodof treating asthma comprising: providing a surface active phospholipid(SAPL) composition as a dry powder, said composition comprising a blendof dipalmitoyl phosphatidylcholine (DPPC) and phosphatidyl glycerol (PG)wherein the PG is present in an amount sufficient that the mixture willspread spontaneously over surfaces of the airways and lungs at normalmammalian blood temperature; and administering said surface SAPLcomposition to an asthma sufferer as an inhalable dry powder; wherebybinding of SAPL to the tissue surfaces of the lungs forms a coating ofSAPL on said surfaces which prevents pollutants and other airbornetriggers from reaching receptors whose irritation would produce an acuteasthma attack, thereby reducing the number of said receptors exposed tonoxious stimuli and reducing hyper-responsiveness of thebroncho-constrictor reflex.